Abstract

Schizophrenia is a psychiatric disorder with symptoms including delusions, social withdrawal and cognitive deficits. The cognitive symptoms respond poorly to current antipsychotic medication and in order to develop new treatments it is necessary to model these deficits in animals. Rearing rats in isolation from weaning causes behavioural, cognitive and neurochemical alterations, some of which have relevance to the symptoms of schizophrenia. The work described in this thesis aimed to further characterise the behavioural and cognitive changes found isolation reared rats.

After five weeks of isolation rats demonstrated increased locomotor activity in a novel environment and a gender specific impairment in recognition memory. After six weeks of isolation rats developed attenuated prepulse inhibition of acoustic startle. Isolation reared rats did not develop impairments in the attentional set shifting test of behavioural flexibility. However, in a further study isolated rats did show deficits in reversal learning (but not acquisition) in the water maze, which were reversed by the pro-cognitive 5-HT6 antagonist Ro 04-6790. Sub-chronic treatment with aniracetam, a modulator of the AMPA receptor had no effect on fear-related memory impairments seen in passive avoidance but aniracetam-treated isolation reared rats were able to discriminate the novel object.

Finally, following controversial reports linking heavy cannabis use with increased risk of schizophrenia, weanling rats were dosed with a component of cannabis, Δ9-tetrahydrocannabinol (THC). The interactions between isolation rearing and two regimens of THC treatment (low: 4x 2mg/kg and high: 8x 5mg/kg) were observed in adulthood. The low dose of THC had no effect on any behavioural test used. The high dose of THC led to impairments in recognition memory but had no effect on attentional set shifting or prepulse inhibition. High-THC and isolation rearing interacted to improve passive avoidance performance in isolates, but impair social rats.

In conclusion, isolation rearing induces varied cognitive deficits which are responsive to nootropic compounds and as such is an important tool in the development of cognition enhancing and antipsychotic drugs.